How is IgG4 disease treated?

IgG4-Related Disease: Diagnosis and Treatment

Corticosteroids are the first-line treatment for IgG4-related disease, with oral prednisolone 40 mg daily for 2-4 weeks followed by a gradual taper over 8-12 weeks being the standard regimen for remission induction. 1

What is IgG4-Related Disease?

IgG4-related disease (IgG4-RD) is a recently described multisystem fibroinflammatory disorder characterized by:

• IgG4-positive lymphoplasmacytic infiltrate in affected organs
• Storiform fibrosis (except in lymph nodes and bone marrow)
• Obliterative phlebitis (except in lymph nodes and bone marrow)
• Elevated serum IgG4 levels in 50-80% of patients

The disease commonly affects:

• Pancreas (IgG4-related pancreatitis/IgG4-RP)
• Biliary tract (IgG4-related sclerosing cholangitis/IgG4-SC)
• Salivary and lacrimal glands
• Retroperitoneum
• Kidneys
• Lungs
• Other organs (aorta, thyroid, meninges, etc.)

Diagnostic Approach

Diagnosis requires a combination of:

1. Clinical features: Organ enlargement, dysfunction, or incidental imaging findings

2. Laboratory findings:

   • Elevated serum IgG4 (>135 mg/dL) in 50-80% of cases
   • IgG4/IgG1 ratio >0.24 improves specificity 1
   • Blood IgG4/IgG RNA ratio >5% has excellent sensitivity (94%) and specificity (99%) 1

3. Imaging findings:

   • MRI/MRCP for biliary involvement
   • CT for pancreatic and other organ involvement
   • PET scanning can identify multisystem involvement 2

4. Histopathology (gold standard):

   • Dense lymphoplasmacytic infiltrate with IgG4+ plasma cells
   • IgG4+/IgG+ plasma cell ratio >40%
   • Storiform fibrosis
   • Obliterative phlebitis

Differentiating IgG4-SC from PSC

Feature	PSC	IgG4-SC
Male sex	+	++
Age	Younger	Older
Pancreatic involvement	+	+++
Raised serum IgG4	+/-	++
>10 IgG4+ plasma cells/HPF in tissue	+/-	+++
IBD association	++	+/-
Steroid response	+/-	++

Treatment Algorithm

Initial Treatment

1. Indications for treatment: Symptomatic disease or risk of organ damage 3

2. First-line therapy:

   • Oral prednisolone 40 mg daily for 2-4 weeks
   • Taper by 5 mg every week over 8-12 weeks 1
   • Monitor clinical response (jaundice resolution, liver biochemistry) and radiological improvement

3. Assessment of response:

   • Repeat imaging at 4-8 weeks
   • Lack of improvement suggests incorrect diagnosis or fibrotic phase 1

Maintenance and Relapse Management

1. Maintenance options:

   • Low-dose prednisolone (5-7.5 mg) reduces relapse rate to 23% vs 58% with complete withdrawal 1
   • Consider immunomodulators (azathioprine 2 mg/kg/day, mycophenolate) for steroid-sparing 3

2. For relapse (occurs in >60% of patients, especially with multiorgan involvement):

   • Reintroduce or increase steroid dose
   • Add immunomodulator if not already on one
   • Consider rituximab for refractory cases (>95% response rate) 1, 4

Important Clinical Considerations

• Steroid complications: New or worsening diabetes occurs in ~40% of patients 4
• Disease monitoring: Serum IgG4 often falls with treatment but should not be used alone to guide therapy 1
• Long-term outcomes: Disease can progress to cirrhosis in 7.7-9% of patients with IgG4-SC 1
• Malignancy risk: Increased risk of malignancy compared to age-matched controls 1
• Pitfalls to avoid:
  • Misdiagnosing as malignancy (especially pancreatic cancer or cholangiocarcinoma)
  • Performing unnecessary surgery
  • Failing to obtain adequate tissue for diagnosis
  • Relying solely on serum IgG4 levels for diagnosis

By following this structured approach to diagnosis and treatment, most patients with IgG4-RD can achieve disease control and prevent permanent organ damage.